Experimental autoimmune encephalomyelitis (EAE) has long been studied as a model for multiple sclerosis. A major focus of research in this model has been the investigation of immunologic mechanisms to suppress the disease process. Oral tolerance is a classic mechanism for the induction of antigen specific peripheral immunologic tolerance, and we have been studying the suppression of the EAE by the oral administration of myelin basic protein (MBP) and myelin antigens. Such studies have direct clinical relevance as there currently are ongoing trials at our institution treating patients with early relapsing remitting multiple sclerosis via oral tolerization to myelin antigens. We have previously shown that oral administration of MBP leads to the generation of CD8+ T cells that adoptively transfer protection and suppress in vitro antigen specific responses. This effect appears to be mediated by an antigen nonspecific factor tentatively identified as TGF-beta which is secreted by CD8+ cells after being triggered by specific antigen. The specific aims of the revised proposal are as follows: 1) What are the characteristics of the cells involved in suppressing EAE following oral administration of MBP (in vitro studies)? 2) What are the in vivo mechanisms of bystander suppression? 3) What are the in vivo cellular mechanisms involved in generating oral tolerance? 4) Investigation of suppression in the relapsing Lewis rat EAE model and in adoptively transferred EAE.